Jay D. Amsterdam: The Paroxetine 352 Bipolar Study Ethical Conduct
Mark Kramer’s reply to Edward Tobe’s comment
I appear to have prompted Edward Tobe’s comment when I replied to Samuel Gershon’s reply to Jay Amsterdam with, “Why isn't there an outcry from every quarter? Why aren't those who perpetrated these crimes against academia, industry and big publishing, outcast – made to pay in some way?”
Of course, my question to Sam was mostly rhetorical, as I’d already cynically concluded years ago in response to Barry Blackwell’s essay (Kramer 2016) that the root of corruption in psychopharmacology is the same unspeakable root that resides generally and indelibly within our species. Yet, Edward Tobe’s thoughtful-flowing comments helped me to validate, contextualize and expand my thinking regarding the anechoic chamber of silence enveloping the detailed evidence compiled and published by Jay Amsterdam, Lemmon McHenry and Jon Jureidini.
I’d not come to personal closure on the “evils” that Jay and Co. had uncovered, as I could not yet understand how I could be anything other than a hypocritical cynic. After all, I’d never rejected the anti-cynical values of fame, power and reputation. But Edward Tobe helped me to see. Maybe because, as Ed hinted, I’d divorced anti-cynical values from my “scientific research” and redirected them to my unconventional career in a harmless niche sector of the music industry, that I maintained integrity as a scientist, lo – even at times as one in big corporate America. And it was there in Industry, by monitoring my non-cynic, I thrived honorably until I could no longer endure, nor fight, the tsunami of corrupt quasi-intellectual distortions coming my way. Fortunately, I had an out, (jazz piano) and took it in a nick of time - just as all had begun to collapse around me.
Until now, I’d not given enough bandwidth to Tobe’s observations on 1) the systematic dehumanization/devaluation of clinical research subjects and programs for minorities (Tuskegee, First Nations, etc.) or 2) the huge, then nearly invisible background framework of government-academia-Industry in which I toiled. That corruption of science could occur in such a framework at all should have been more on my radar. But it was not until my friend Jay Amsterdam engaged me on GSK “ghostwriting,” long after I in practical terms vacated our field, that I began to see the bigger picture of the world I blindly inherited as I worked.
I only ever regarded my work in clinical research in this way: 1) if I could get clear efficacy and safety signals, my efforts might help our science, 2) humanity would be the beneficiary and 3) I would have fulfilled a reason for my education, repaid the care of my mentors and perhaps my own arising. To be clear, I did care about being visible. But acquiring a fortune was never my aim. With advancing age, I can see all I ever wished was to bring an important idea into the world, but not requiring a trace of personal identity. I know that this is the case, now.
As a then modern clinical trial-Meister (1979-~2001, also experienced in preclinical pharmacology) - but not initially realizing that the age of the “professional patient” had been accelerating on my watch - my conscience had been very clear about my work. In fact, when some of our clinical trials began to fail (i.e., neither placebo, experimental or standard controls differentiated), I felt quite outraged that my sleepless efforts must have been compromised by investigators and pseudo-patients alike.
I knew what I was doing and why. All through my clinical research careers, I carefully followed FDA required/sanctioned DSM Dx criteria. Even so, I very well understood that: 1) without clear biological markers of mental illness, we were still only doing the best we could, 2) the practice of medicine in the real world is more art than science, 3) placebo is at times powerful “medicine” across many fields of medicine and 4) especially for un-biomarked conditions, randomized controlled trials cast a very broad net; on that basis (in part) results can be expected to display smallish effect sizes in which an individual patient type in clinical practice may not benefit from the treatment under study. That’s why replication is so important regarding validating a small but basic signal.
Nevertheless, with all the above-mentioned in awareness, I and my team humbly tried to introduce a brand-new antidepressant drug mechanism-class. This had been inspired by my “A-HA” moment that maybe people with overexpressed NK1 (Substance P) receptors in limbic-related branches of archaic pain pathways might experience (sans somatic pain) irrational anxiety or depression. (One weekend, I asked for and received supportive preclinical demonstrations of this idea through Nadia Rupniak’ s guinea pig pups who yelp when separated from their mothers. In this, their apparently distressed state, the animals clearly intracellularly internalize Substance P. But both this peptide internalization, as well as behavioral evidence of stress were dose-relatedly abolished by pretreatment with NK1 antagonists, neither with observable effects on locomotor or other activity, nor biochemically typical interactions with monoaminergic systems. I eventually shared evidence that the class of NK-1 antagonists (originally preclinically, seldom clinically, demonstrated as a new kind of non-addictive analgesic) to maybe reduce suffering for some highly impaired people with real (Major) depression and anxiety (Kramer, Cutler, Feighner et al. 1998.) That would have been good. But for me, the potential importance of the work was primarily that such a new heuristic mechanism might help provide a clue that would help the field of biological neuroscience to move incrementally forward.
I did continuously irrationally worry that NK1 [Substance P] antagonism, a mechanism seemingly so closely tied to survival and immune response, might have long term unfavorable consequences if blocked. But that had not yet been the case in long term sub chronic clinical extensions. Mechanistically, it was beginning to look like Substance P was a master regulator of NE, 5HT, DA (either in neurons, glia or BBB) and also interacted with GABA/Glutamate. But most preclinical research stopped on neurokinin systems once my past company failed to commercialize the mechanism as an antidepressant drug.
Many here may not have heard of this NK1-antagonist antidepressant discovery; if they had, they are likely confused about it. Therefore, years after my company, its neuroimaging arm and a couple of paid KOLs had “screwed the pooch,” it was only upon the fifth large study replication of NK-1 antagonism antidepressant activity (third independent company, five different molecules), many years later I decided in 2017 to co-author a summary entitled: NK1 receptor antagonists for depression: Why a validated concept was abandoned (Rupniak and Kramer 2017). To me, what had occurred more than a decade ago had been a gut wrenching immoral abandonment (and distortion) of science. This was based in part on the opaque data and beliefs of the neuroreceptor PET imaging industry. (There had already been some evidence as presented in a PowerPoint presentation on the internet that NK1 receptors tended to increase in emotional brain regions of patients with severe depression. Yet, that was taken down when the truth became inconvenient, i.e., when the company underdosed its huge and failed Phase III program! I’d left a couple of years earlier after objecting to the proposed Phase III low dose – a dose that might have been marginally profitable [manufacturing-wise] compared with the higher effective exposure, previously observed in the clinic. The formulation and dose the company tested in its huge Phase III provided ~40% less than the empirically required systemic exposure for observed efficacy obtained previously in a much smaller, more tightly recruited, monitored and properly powered patient sample.)
Realistically, just about the time I exited hands-on clinical research, the entire clinical arm of neuropsychopharmacology drug trials had already died at the hands of corruption. There is now just about no conceivable reliable method by which we can recruit an authentic relatively large homogeneous population suffering with anything like the mental “disorders” that spawned our field.
Aside from its ancient origins in botany and mycology, the entire field of modern neuropsychopharmacology (including endocrinology) is very young/immature and has been tormented by critics from its outset. Who would not agree? Yet, this wonderful INHN website is a repository for many of the roads (many chaotic) that have guided us to this point. I’m not sure who might have the bandwidth to make INHN more easily discoverable and attractive in this new age, but I know I do not. Certainly, Tom Ban (RIP), Barry Blackwell, Sam Gershon, Carlos Morra, Peter Martin and many others have carried the torch admirably. It deserves even more.
Despite the omnipresent corruption brought into bold relief by Professor Jay et al., I do envision breakthroughs in so-called mental illness from realms containing an entirely new scientific framework that we “do not even know, we do not know.” After all, this is generally the manner through which the most stubborn of obstacles to reason and acquisition of knowledge are overcome: indirectly. We forget. And when that occurs, it will not take much for corruption to start up again.
I was truly moved by Edward’s closing, “Mark Kramer’s success was to follow a path of dignity possessing both scientific and musical talent. To be able to not only hear but to listen to the music of life as we travel through this voyage is an accomplishment.” It is in line with his poetically crafted foregoing, that “I,” while claiming little credit or success on the roads so far travelled, nevertheless feel tremendous gratitude towards a “presence” which I would term the “unknowable” (cause or configuration) that enabled this consciousness/awareness to arrive here at all, to evolve a bit, and to be shared with those of my fellow travelers. What a journey! Be well. Thank you, Ed. Thank you INHN.
References:
Kramer M. Mark Kramer Music. mark-kramer.com/.
Kramer M. Commentary. Innovation, propaganda, and jail time. Barry Blackwell: Corporate Corruption in the Psychopharmaceutical Industry. inhn.org.controversies. October 13, 2016.
Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G, Snavely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Carlson EJ, Hargreaves RJ, Rupniak NM . Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 1998; 281:1640-5.
Rupniak NMJ, Kramer MS: NK1 receptor antagonists for depression: Why a validated concept was abandoned. J Affect Disord 2017;223:121-5.
July 28, 2022